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Activation of Ca2+-independent phospholipase A2β (iPLA2β) leads to production of proinflammatory prostaglandins E2 (PGE2) and diols generated by cyclooxygenase (COX) and soluble epoxide hydrolase (sEH), respectively, and we reported that decreasing iPLA2β reduces T1D incidence. Importantly, we find that inhibiting PGE2 signaling with an EP4r antagonist or sEH inhibitor mitigates immune cell inflammatory phenotype. We therefore tested if inhibiting PGE2 signaling (with grapiprant, GP) or sEH (with uEC/u5026) can prevent T1D onset. Starting at 4-weeks of age, NOD mice were treated with vehicle (PEG), GP, or EC and TID onset (≥275 mg/dl glucose) was monitored over 32 weeks of age. Further, as we noted that the production of proinflammatory PGs increases early and higher DHETs/EETs ratios occur closer to predicted T1D onset age, a 4th group was treated with GP starting at 4 weeks and EC added at 8 weeks of age. As expected, T1D incidence was 85% in PEG-treated NOD. Alone, GP reduced incidence modestly and EC5026 was without effect. However, the combination of both significantly reduced incidence. Intriguingly, near T1D onset age there was evidence of higher resolvins (Rvs), which are generated in response to inflammation to affect resolution. We therefore tested the effects of RvD2 and RvE1 supplementation and found that RvD2 was without effect. In contrast, RvE1 produced a significant decrease in incidence, compared with vehicle-treated NOD. In contrast to vehicle-treated diabetic NOD, circulating insulin levels were measured in nondiabetic NOD from both treatment regimens and there was no discernible drug cytotoxicity, as reflected by pathological assessments of pancreas, liver, kidney, and heart. These findings suggest consideration of targeting early inflammation and subsequent resolution phases to counter T1D development. Further, they provide a strong rationale for employing novel combination regimens to modulate select inflammatory and resolving lipid signaling to delay or prevent or T1D onset. Disclosure T. White: None. A. Almutairi: None. Y. Tusing: None. B. Hammock: Board Member; Eicosis. C. McReynolds: Employee; EicOsis. Consultant; Inipharm. D. Stephenson: None. C.E. Chalfant: None. S. Ramanadham: None. Funding NIH/NIAID 1R21AI169214-01JDRF 2-SRA-2022-1210-S-B3-SRA-2023-1362-S-B1-INO-2023-1344-A-NNIH/NIAID 1 R21 AI 146743UAB Department of CDIBUAB Comprehensive Diabetes Center
WHITE et al. (Fri,) studied this question.